RhoA balances microglial reactivity and survival during neuroinflammation
Abstract Microglia are the largest myeloid cell population in the brain. During injury, disease, or inflammation, microglia adopt different functional states primarily involved in restoring brain homeostasis. However, sustained or exacerbated microglia inflammatory reactivity can lead to brain damag...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-10-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06217-w |
| _version_ | 1797397733613502464 |
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| author | Renato Socodato Artur Rodrigues-Santos Joana Tedim-Moreira Tiago O. Almeida Teresa Canedo Camila C. Portugal João B. Relvas |
| author_facet | Renato Socodato Artur Rodrigues-Santos Joana Tedim-Moreira Tiago O. Almeida Teresa Canedo Camila C. Portugal João B. Relvas |
| author_sort | Renato Socodato |
| collection | DOAJ |
| description | Abstract Microglia are the largest myeloid cell population in the brain. During injury, disease, or inflammation, microglia adopt different functional states primarily involved in restoring brain homeostasis. However, sustained or exacerbated microglia inflammatory reactivity can lead to brain damage. Dynamic cytoskeleton reorganization correlates with alterations of microglial reactivity driven by external cues, and proteins controlling cytoskeletal reorganization, such as the Rho GTPase RhoA, are well positioned to refine or adjust the functional state of the microglia during injury, disease, or inflammation. Here, we use multi-biosensor-based live-cell imaging approaches and tissue-specific conditional gene ablation in mice to understand the role of RhoA in microglial response to inflammation. We found that a decrease in RhoA activity is an absolute requirement for microglial metabolic reprogramming and reactivity to inflammation. However, without RhoA, inflammation disrupts Ca2+ and pH homeostasis, dampening mitochondrial function, worsening microglial necrosis, and triggering microglial apoptosis. Our results suggest that a minimum level of RhoA activity is obligatory to concatenate microglia inflammatory reactivity and survival during neuroinflammation. |
| first_indexed | 2024-03-09T01:14:26Z |
| format | Article |
| id | doaj.art-3994b4d2fd7c4a6cbc6d01adeccdeaee |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-09T01:14:26Z |
| publishDate | 2023-10-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-3994b4d2fd7c4a6cbc6d01adeccdeaee2023-12-10T12:33:22ZengNature Publishing GroupCell Death and Disease2041-48892023-10-01141011510.1038/s41419-023-06217-wRhoA balances microglial reactivity and survival during neuroinflammationRenato Socodato0Artur Rodrigues-Santos1Joana Tedim-Moreira2Tiago O. Almeida3Teresa Canedo4Camila C. Portugal5João B. Relvas6Institute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of PortoInstitute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of PortoInstitute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of PortoInstitute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of PortoInstitute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of PortoInstitute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of PortoInstitute of Research and Innovation in Health (i3S) and Institute for Molecular and Cell Biology (IBMC), University of PortoAbstract Microglia are the largest myeloid cell population in the brain. During injury, disease, or inflammation, microglia adopt different functional states primarily involved in restoring brain homeostasis. However, sustained or exacerbated microglia inflammatory reactivity can lead to brain damage. Dynamic cytoskeleton reorganization correlates with alterations of microglial reactivity driven by external cues, and proteins controlling cytoskeletal reorganization, such as the Rho GTPase RhoA, are well positioned to refine or adjust the functional state of the microglia during injury, disease, or inflammation. Here, we use multi-biosensor-based live-cell imaging approaches and tissue-specific conditional gene ablation in mice to understand the role of RhoA in microglial response to inflammation. We found that a decrease in RhoA activity is an absolute requirement for microglial metabolic reprogramming and reactivity to inflammation. However, without RhoA, inflammation disrupts Ca2+ and pH homeostasis, dampening mitochondrial function, worsening microglial necrosis, and triggering microglial apoptosis. Our results suggest that a minimum level of RhoA activity is obligatory to concatenate microglia inflammatory reactivity and survival during neuroinflammation.https://doi.org/10.1038/s41419-023-06217-w |
| spellingShingle | Renato Socodato Artur Rodrigues-Santos Joana Tedim-Moreira Tiago O. Almeida Teresa Canedo Camila C. Portugal João B. Relvas RhoA balances microglial reactivity and survival during neuroinflammation Cell Death and Disease |
| title | RhoA balances microglial reactivity and survival during neuroinflammation |
| title_full | RhoA balances microglial reactivity and survival during neuroinflammation |
| title_fullStr | RhoA balances microglial reactivity and survival during neuroinflammation |
| title_full_unstemmed | RhoA balances microglial reactivity and survival during neuroinflammation |
| title_short | RhoA balances microglial reactivity and survival during neuroinflammation |
| title_sort | rhoa balances microglial reactivity and survival during neuroinflammation |
| url | https://doi.org/10.1038/s41419-023-06217-w |
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